The present invention relates to a process for selective production of a 2-.alpha.-O-glycoside compound of sialic acid useful as a starting material or an intermediate for various medicines and biochemical reagents such as gangliosides or analogues thereof.
Sialic acid is present in various tissues of living organisms and is normally present in the portion which constitutes a sugar chain as its constitutional unit through glycosidic linkage. Sialic acid is an important constitutional component of glycolipid or glycoprotein. Therefore, for the purpose of studying its function and from the viewpoint of application in medical field because of the recent attention to various physiological activities of gangliosides, investigation has been intensively made on synthesis of analogues, derivatives, glycosides of sialic acid and sialooligosaccharides have been synthesized. However, the study is only beginning and there are many problems in synthesis to be solved.
One of the problem is in conversion of sialic acid to an .alpha.-O-glycoside. That is, as is well known, in all of the naturally occurring sialic acid derivatives except for cytidine monophosphate-N-acetylneuramic acid, sialic acid bonds to sugar chain, etc. through .alpha.-O-glycoside linkage, but there have been no examples of selectively producing .alpha.-O-glycosides of sialica acid. That is Chem. Ber., 99, 611-617 (1966) discloses reacting a 2-.alpha.-Cl derivative of sialic acid as a sugar donor for formation of glycoside with a sugar derivative as an acceptor. However, the resulting glycoside is a mixture of .alpha.-glycoside and .beta.-glycoside. Furthermore, Carbohydr. Res., 146, 147-153 (1986) and Carbohydr. Res., 163, 209-225 (1987) disclose examples of reacting the above sugar donor with a secondary hydroxyl group of sugar derivative which is an acceptor, using Hg(CN).sub.2 /HgBr.sub.2 and Ag.sub.2 CO.sub.3 /AgClO.sub.4 as a catalyst, respectively. The products are also mixtures of .alpha.-glycoside and .beta.-glycoside in which proportion of .alpha.-glycoside is smaller than that of .beta.-glycoside in both cases. Moreover, Tetrahedron Lett., 27, 5229-5232, 5233-5236 (1986) and Tetrahedron Lett., 28, 6221-6224 (1987) disclose production of a mixture comprising a higher proportion of .alpha.-glycoside and lower proportion of .beta.-glycoside using a sialic acid derivative having a substituent at 3-position in an attempt to preferentially produce .alpha.-glycoside. However, the product is still not satisfactory in stereoselectivity and yield and especially in the case of the reaction with secondary hydroxyl group, this cannot be practically utilized.
The inventors have already found that when an .alpha.-SMe derivative or .beta.-SMe derivative of sialic acid as a sugar donor is reacted with a straight chain primary alcohol in dichloromethane in the presence of dimethyl(methylthio)sulfonium triflate (hereinafter referred to as "DMTST"), the corresponding .beta.-O-glycoside of sialic acid was selectively obtained and have filed a patent application therefor. (Japanese Patent Kokai No. 63-41494).
Thus, most of O-glycosides of sialic acid which were synthetically obtained were mixtures of .alpha.-glycoside and .beta.-glycoside and a specific case (in the case of primary hydroxyl group), only .beta.-glycoside was selectively obtained while there have been no examples of obtaining .alpha.-glycoside selectively and in high yield. In the case of secondary hydroxyl group, there have been no examples of obtaining .alpha.-glycoside and .beta.-glycoside selectively and in high yield.